This is a competitive renewal for Penn's P30 NIDDK Center on Molecular Therapy for Cystic Fibrosis and Genetic Diseases which has been in place since 1993. At the last renewal we shifted our strategy from a focus on clinical trials to vector discovery and distribution with an increased emphasis on immunology and animal models. This has had the desired result of substantially fueling a robust pipeline of promising preclinical programs that are entering clinical trials with better technology and an enhanced understanding of vector biology necessary for clinical success. With encouragement from NIDDK, we expanded access to our Cores to investigators outside of Penn to establish important strategic collaborations. During this cycle of the grant, Vector Core services increased from 576 in year 11 of the grant to 1458 projected for the current year (year 15). The substantial expansion of gene and cell therapy research associated with our Center is due in large part to the availability of new AAV and lentiviral technology discovered at Penn and distributed through our Vector Core. An important aspect of this expansion has been in the area of immunology that has emerged as a major impediment to success. The Center has aggressively recruited the participation of scientists interested in applied immunology and genetic vaccines to focus on issues relevant to gene and cell therapy. The current research base is substantial and strong across all areas relevant to the Center. Current total annual direct costs of grants awarded to Center Participants has been organized into the following three areas: Genetic Diseases, Stem Cells and Gene Transfer - $49 mil; Cystic Fibrosis - $8.6 mil; and Immunology and Vaccines -$14.9 mil. The Pjlot Grant program remains strong and has been useful in supporting young investigators and encouraging the participation of new investigators. Important recruitments at Penn have provided the opportunity to enhance leadership of the Center's Cores. This application requests support for Pilot Grants as well as the following Cores: Vector, Immunology, Cell Morphology and Animal Models.